Physiology, gonadotropin-releasing hormone (2023)

Introduction

Gonadotropin-releasing hormone (GnRH), a decapeptide, is part of the hypothalamic-pituitary-gonadal axis, and being part of this system makes it essential for human reproduction. Since its discovery by a group of Nobel laureates Andrew V. Schally in 1971 from the hypothalamus of the pig, one of the first releasing hormones from the hypothalamus has been the center of attention of researchers because of its central role in reproduction, not just in humans, but also in all vertebrates.

More than 20 different GnRH primary structures and their receptors have been studied in different species. Compared to GnRH I, GnRH II is not widespread. It is found in the central nervous system, where it appears to act as a neuromodulator of sexual behavior, and in tissues of the female reproductive system, such as the endometrium, ovaries, and placenta (and in tumors derived from these tissues). GnRH I & II are present in humans, GnRH-I (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly·NH2) is mainly discussed in this review because it is the major isoform that has the most significance physiological in humans.

Gonadotropin-releasing hormone (GnRH) is a crucial substance in the hypothalamic-pituitary-gonadal (HPG) axis in humans. GnRH production occurs in neurons of the hypothalamus and causes the downstream production of sex hormones by the gonads. This hormone ultimately regulates the onset of puberty, sexual development, and ovulation cycles in women. Intrinsic or extrinsic disturbances in this pathway can lead to the development of pathological conditions in humans. Pharmacological analogues of GnRH are useful in the treatment of gynecological diseases because of their ability to block estrogen secretion by the ovary. Emerging evidence suggests that stimulation of tumor GnRH receptors induces antiproliferative and antimetastatic activity, making it a potential therapeutic target.[1]This review will discuss the cellular and genetic characteristics of GnRH, as well as its physiological and pathophysiological mechanisms in humans.

issues of concern

GnRH is crucial because it has implications in the pathogenesis of central hypogonadism. GnRH and its analogues are used as a treatment modality in infertility, endometriosis, central precocious puberty, and hormone-dependent malignancies such as breast and ovarian cancer.

cellular level

Genetic:

In humans, the GnRH I gene, composed of four exons and three introns, is on the short arm of chromosome 8 (8p21-p11.2). The GnRH journey begins at the medial olfactory placode. From here it travels along the olfactory bulb to reach the hypothalamus. GnRH is then secreted in a pulsatile manner into the pituitary portal circulation, where it reaches its primary destination, the pituitary gland. Here it binds to the gonadotropin-releasing hormone receptor (GnRHR), which is a G protein-coupled receptor, on the gonadotrophic cells of the pituitary gland. Binding of GnRH to GnRHR initiates downstream signaling of the primary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[2]

Several genes aid in the process of development and differentiation (fibroblast growth factor receptor 1 (FGFR1) and its ligand fibroblast growth factor 8 (FGF8), heparin sulfate 6-O-sulfotransferase 1 (HS6ST1) and hormone factor nasal embryonic LH (NELF) releaser), migration (NOS1, semaphorin 3A (SEMA3A), prokinetic 2 (PROK2) and prokinetic receptor 2 (PROKR2)) and neuronal stability (SEMA3E).

Neuroanatomy:

GnRH cell bodies are in the medial preoptic area (POA) and arcuate/infundibular nucleus of the hypothalamus, forming a neuronal network with projections to the median eminence. GnRH secretion occurs from the median eminence into the fenestrated capillaries of the portal circulation and is then transported to the pituitary gland. In humans, estimates of the number of GnRH neurons range between 1,000 and 1,500. Co-localization of GnRH neurons with other central regulators allows the GnRH network to be influenced by a variety of neuroendocrine and metabolic inputs.[3]

Gonadotropin Releasing Hormone Receptor (GnRHR):

The location of the GnRH receptor (GnRHR) is in the anterior pituitary and belongs to the family of G protein-coupled receptors. Its seven transmembrane domains describe this class of receptors. These receptors, when bound by an activating subunit, undergo conformational change and activate intracellular pathways that lead to modulation of genes in a target cell through phosphorylation events. Activation of receptors leads to the formation of clusters of receptors. These receptor clusters can be transported to the cell surface or degraded in lysosomes after they have been internalized. A short intracellular carboxy-terminal tail characterizes this particular receptor. This structure helps to prevent desensitization and delay receptor internalization. GnRHR binds to a member of the G protein family called Gq. The Gq protein cleaves a molecule called phosphatidylinositol-4-5-bisphosphate (PIP). PIP cleavage results in the formation of inositol phospholipid (IP3) and the cleavage of the PIP2 molecule. IP3 stimulated the endoplasmic reticulum to release calcium into the cytosol. DAG activates the protein kinase C (PKC) signaling cascade. Protein kinase C then proceeds to stimulate the MAP kinase and ERK1/2 cascades. As a minor action, GnRHR activation can activate cAMP and protein kinase A (PKA) signaling cascades, which occur via Gs and the calcium-calmodulin system. Once activated, these pathways lead to the biosynthesis and secretion of gonadotropins.[4][5]

Development

During embryonic life:

The embryonic development of GnRH neurons is closely linked to the olfactory system. Neurons that release GnRH use vomeronasal and olfactory axons as a scaffold to migrate. Once in the forebrain, they travel to their final position via a branch of the vomeronasal/terminal nerve. GnRH neuronal development occurs between the 5th and 16th embryonic week (SE). In the middle of the 5th EW to start the 6th EW, GnRH neurons can be detected in the olfactory placode. By mid-6 EW, these neurons begin to migrate near the nerve terminal where they enter the forebrain.

By the 9th EW, these neurons will reach the hypothalamus. Between the 13th and 16th week of gestation, migration is considered complete. GnRH levels can be detected at 10 weeks of gestation, but LH and FSH levels can only be detected after 13 weeks of gestation, the reason for the late occurrence of LH and FSH is the formation of vascular connections between the pituitary gland and the hypothalamus for about 10 to 13 weeks, after which GnRH can reach the pituitary and cause the release of FSH and LH.

GnRH levels gradually increase and peak at mid-gestational age, after which they gradually decline towards the end of the gestation period due to the negative feedback effect of circulating placental steroids. At birth, the development of GnRH neurons is complete, but functional maturation of the synaptic connection is achieved later in life, especially during puberty. After birth, these levels remain elevated for two years in girls and six months in boys. The mechanism of GnRH suppression after birth is still unknown, but certain neurotransmitters such as GABA and neuropeptide Y appear to play an important role in GnRH suppression before puberty.

During puberty:

This temporary pause in GnRH release ends at puberty, and recent studies have shown that Kisspeptin neurons are responsible for activating the hypothalamic-gonadotropic axis that causes GnRH release at puberty. Initially, at puberty, GnRH is released in low-frequency pulses during the night, but after maturation of synaptic connections, it corresponds to the adult pattern. In men, GnRH pulses occur after 2 hours, while in women they change according to the phases of the menstrual cycle. It is clear that the episodic release of GnRH is a general phenomenon. Fluctuations in the amplitude and frequency of GnRH surges also play a critical role in initiating the hormonal loads that regulate the menstrual cycle. The frequency of GnRH surges is reduced by testosterone and progesterone and increased by estrogens. The frequency (1 pulse of GnRH/60 to 90 minutes) during the late follicular phase of the menstrual cycle increases, culminating in the LH surge. In the secretory phase of the menstrual cycle, the effect of progesterone decreases in frequency (1 pulse of GnRH/200 minutes). At the end of the menstrual cycle, when the secretion of progesterone and estrogen decreases, the frequency increases. The sensitivity of gonadotrophs increases significantly during the mid-cycle LH surge; this is due to exposure to GnRH pulses at a specific frequency, which describes a critical auto-initiating effect of GnRH that produces a maximal LH response. Changes in GnRH frequency and amplitude thus alter gonadotropin synthesis and LH and FSH release.

During menopause:

Changes in GnRH release in the perimenopausal period. As the number of follicles recruited during each menstrual cycle decreases near menopause, the amount of estrogen produced also decreases, resulting in reduced estrogen negative feedback on GnRH release, leading to an increase in the frequency of GnRH release (every 55 minutes) and amplitude . As women age from 50 to 80 years, the frequency of GnRH pulses decreases by 35%.

Organ systems involved

GnRH is a central regulator of the hypothalamic-pituitary-gonadal (HPG) axis. The neurons that produce GnRH are in the hypothalamus, specifically in the infundibular nucleus. Once secreted, GnRH acts on the anterior pituitary gland where follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are secreted and modulates the production of sex steroids by the gonads.[6]

To work

As GnRH is a peptide hormone, its receptors are located on the cell membrane.

The GnRH receptor (GnRHR) is part of a superfamily of rhodopsin-like G-protein coupled receptors. These receptors have a hydrophilic extracellular domain, an intracellular domain and finally a hydrophilic transmembrane domain. This transmembrane domain spans the cell limb a total of seven times. These receptors, once bound to the hormone, undergo conformational changes that activate an intracellular signaling cascade and, through various phosphorylation events, eventually lead to transcriptional modulation of genes in the target cell. Activation of these receptors induces the formation of groups of receptors that become internalized in the cell, where they are then transported back to the cell surface or degraded in lysosomes. The relatively short intracellular carboxyterminal tail of the GnRH receptor distinguishes it from other G protein-coupled receptors. This tail slows receptor internalization and prevents rapid desensitization. GnRH receptors are coupled to the Gq protein. This process takes place in the following steps.

GnRH or GnRH agonist binds to GnRH receptors located on pituitary cells.

1. This results in phosphorylation of GDP and formation of GTP, GTP binds to the alpha subunit of the Gq protein, and the alpha subunit along with bound GTP is separated from the G protein and binds to phospholipase C.

2. Phospholipase C breaks down PIP (phosphoinositol diphosphate) into IP (inositol triphosphate) and DAG (diacyl glycerol).

3. DAG causes additional activation of protein kinase C.

   (Video) Gonadotropin-releasing hormone (GnRH) agonists

4. Protein kinase C causes phosphorylation of intracellular proteins.

5. Inositol triphosphate binds to receptors on the membrane of the endoplasmic reticulum and causes the release of calcium into the cytoplasm.

6. Proteins phosphorylated by protein kinase C serve as an intracellular signaling pathway for the mitogen-activated protein kinase (MAPK) pathway, including ERK, JNK, and p38 MAPK.

7. Calcium released into the cytosol binds to calmodulin, which causes increased protein phosphorylation via activation of another set of protein kinases, performs intracellular transport functions, improves cell metabolism, and exocytosis of hormone-storing vesicles.

Another point worth remembering is that although most GnRH receptors are Gq protein-coupled, few are Gs-protein-coupled as well. This Gs/cAMP pathway is involved in the initial pituitary gonadotropin response to GnRH or GnRH analogues and in the further regulation of pituitary gonadotropin synthesis and secretion.

Differential regulation of LH and FSH:

Although GnRH acts on pituitary cells to increase gonadotrope release, its effect is not the same as FSH and LH. The frequency of the GnRH pulses selectively increases the transcription of the gonadotropic gene. Fast pulses promote LH formation and secretion, while slow pulses promote FSH formation and secretion. The researchers observed that even blocking the GnRH agonist through the administration of GnRH antiserum also has a differential effect on FSH and LH, resulting in the absence of LH pulses for 24 hours, while FSH levels remain detectable for a period of time. longer period.

Mechanism

GnRH secretion and pulsatility:

Secretion of GnRH into pituitary blood occurs in two ways:

• Burst mode: refers to the high frequency or continuous release of GnRH in the preovulatory phase of the menstrual cycle.

• Pulsed mode: refers to the release of GnRH at regular intervals and occurs in both men and women, but the frequency of release is different in men and women. In women, the frequency of GnRH release changes throughout the menstrual cycle. One pulse every 1 to 2 hours in the follicular phase, continuous in the preovulatory phase, then decreasing to 1 pulse every 4 hours in the secretory phase.

The actual location and origin of the pulsatile release of GnRH is not fully understood. Episodic multiunit electrical activity in the medial basal hypothalamus (MBH) is correlated with LH release, suggesting that the 'GnRH pulse generator' is either anatomically located in the MBH or closely linked to it neurohormonally. GnRH neurons themselves show intrinsic neuronal activity. Physiologically, the pulsatile release of GnRH depends on a complex interaction between glutaminergic neurons, GnRH neurons and KNDy neurons.

Regulation of GnRH release:

GnRH neurons respond to sex steroids, glucocorticoids, inflammation, stress, drugs, body metabolism and nutrition, modulating their release in response to these stimuli. GnRH neurons do not respond directly to these stimuli. Instead, another set of neurons called KNDy neurons, which act as a bridge between GnRH neurons and environmental and internal stimuli, are primarily responsible for this communication and therefore for regulating GnRH release. The discovery of KNDy neurons led to a new understanding of the regulation of GnRH release.

KNDy neural system:

KNDyneuron is a combination of neurons that secrete kisspeptin, neurokinin B and dynorphin. These neurons are afferent to GnRH neurons and act as a bridge between various modulators of GnRH release and GnRH neurons. Input from KNDy neurons to GnRH neurons is physiologically essential for proper functioning of GnRH neurons.

• Kisspeptina:is a polypeptide (145 amino acids) that binds to G protein-coupled receptor 54 (GPR54). About. 50 to 75% of GnRH neurons express the kisspeptin receptor. Kisspeptin-secreting neurons in the arcuate and anteroventral periventricular nuclei (AVPV) of the hypothalamus. AVPV neurons are more abundant than arcuate kisspeptin neurons. However, the arcuate neurons are closer to the GnRH neurons located in the median eminence. Kisspeptin acts at the level of the hypothalamus, stimulating the secretion of GnRH. In recent studies, it has also been shown that kisspeptin can also bind to pituitary cells to cause an increase in LH release.

Kisspeptin neurons also have receptors for sex steroids and therefore modulate the release of GnRH from the hypothalamus. A very interesting phenomenon shown by kisspeptin neurons issexual dimorphism, The expression of the KISS-1 gene is under the control of estrogen and androgens. A man's arcuate nuclei contain more kisspeptin neurons and are under the influence of androgens, whereas a woman's AVPV has more kisspeptin neurons and are mostly under the influence of estrogen. It is primarily the reason for estrogen's inability to cause an increase in GnRH in men.

• Neurocinina B:Neurokinin B belongs to the tachykinin family of peptides and stimulates TACR3 receptors, neurokinin stimulates kisspeptin neurons and even leads to the release of GnRH. This neurotransmitter is also physiologically important, as some patients with hypogonadotropic hypogonadism have missense mutation involving TAC3 (gene that encodes neurokinin B) and TACR3 (gene that encodes neurokinin B receptor).

• dynorphin: Opioids are involved in the regulation of the hypothalamic-pituitary-gonadal axis, as they inhibit kisspeptin neurons and modulate the release of GnRH.

All three neurons communicate via neuron-neuron and neuron-glia gap junctions to modulate GnRH release. Kisspeptin neurons have receptors for neurokinin (stimulatory) and dynorphin (inhibitory). While kisspeptin receptors are located on GnRH neurons, stimulation of these receptors results in the release of GnRH. However, continuous stimulation of GnRH neurons with kisspeptin results in desensitization and downregulation of kisspeptin receptors.

related test

Pituitary portal blood sampling is challenging and difficult due to its short half-life (2 to 4 minutes) and limited to pituitary blood only. Luteinizing hormone levels are therefore measured as a surrogate for measuring GnRH concentration.

pathophysiology

Diseases related to the migration of defective GnRH neurons:

Kallmann syndrome: Characterized by a combination of hypogonadotropic hypogonadism and anosmia

Idiopathic hypogonadotropic hypogonadism: Characterized by hypogonadotropic hypogonadism without anosmia due to prokinetic gene mutations (PROK 1 and PROK 2)

clinical significance

Several feedback mechanisms in humans regulate GnRH activity and have consequences for sexual development, lactation, menstruation, and fertility. Prolactin is a hormone that has inhibitory effects on GnRH, thus inhibiting the production of FSH and LH by the pituitary gland. In women, this inhibition of ovulation leads to amenorrhea, which acts as a physiological contraceptive. In addition to lactation in women, inhibition of GnRH by prolactin can result in infertility in men due to reduced spermatogenesis.[7]

Pharmacologically, GnRH agonists are associated with a decrease in uterine fibroid volume and have been used as a presurgical treatment.[8]Leuprolide, a GnRH receptor agonist, is used to treat prostate cancer, which has replaced the previous treatment of surgical castration. Leuprolide is also used to treat endometriosis, infertility, and precocious puberty. Since this medication and other GnRH analogues cause hypogonadism, some common side effects are hot flashes, erectile dysfunction, loss of libido, depression, nausea, diarrhea and weight gain.[9]GnRH antagonists have been shown to be effective in controlling ovarian stimulation, making them useful in reproductive medicine.[10]

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De Falco M, Pollio F, Pontillo M, Ambrosino E, Busiello A, Carbone IF, Ciociola F, Di Nardo MA, Landi L, Di Lieto A. [GnRH agonists and antagonists in the preoperative therapy of uterine fibroids: review of the literature].Minerva gynecologist.December 2006;58(6): 553-60.[PubMed: 17108883]

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(Video) Endocrine System: Follicle Stimulating Hormone, Luteinizing Hormone, Prolactin (v2.0)